Despite the use of antibiotics and vaccines, Streptococcus pneumoniae (pneumococcus) remains a leading cause of community acquired pneumonia and mortality. Pneumococcal strains are maintained in the population as commensal colonizers of the mucosal surfaces of the upper respiratory tract (URT), which is a precursor to infection of the lower respiratory tract (LRT). Research to date indicates that the pneumococcus has a variety of interactions with the host immune system that are dictated by bacterial as well as host factors, and the anatomical location of the interface. Host factors that lead to the clearance of the bacterium from its commensal niche on the mucosal surface of URT are not well defined. Moreover, it is often the exuberance of the host inflammatory response that leads to morbidity and mortality in the case of invasive pneumococcal infection in the LRT. My preliminary data demonstrate an important role for macrophage migration inhibitory factor (MIF), a cytokine and upstream mediator of the innate immune response, in pneumococcal infection. In a model of nasal colonization with the organism, I have shown that MIF-deficient mice have a prominent defect in the ability to clear URT pneumococcal colonization. In contrast, MIF seems to play a detrimental role in murine LRT infection with pneumococcus. I have demonstrated that presence of MIF in this model is associated with increased local cytokine production and neutrophil influx, resulting in lung tissue destruction, bacterial dissemination, and greater mortality. My hypothesis for this K08 proposal is that MIF has a dual role in pneumococcal pathogenesis - it is necessary for macrophage mediated clearance of URT colonization, but also promotes inflammatory tissue damage in response to invasive infection in the LRT. In Aim#1, I will investigate the mechanism by which MIF promotes clearance of pneumococcal colonization in the URT by examining the role of MIF in macrophage recruitment, activation, and function. In Aim#2, I will explore the contribution of MIF to pathogenic neutrophil recruitment and activation in the LRT. At Yale, I began my training in research methodology and innate immunity to infectious pathogens as a PhD candidate as well as an infectious disease fellow in the laboratory of Dr. Richard Bucala, who serves as my co-mentor for this proposal. Now as a post-doctoral researcher at the University of Pennsylvania, with Dr. Jeffrey Weiser as my primary mentor, I plan to examine the mechanisms by which the immune system interacts with pneumococcus from colonization to disease. I have assembled a mentorship committee as well as a program of training throughout the course of this proposal that will serve as the basis for my career as an independent investigator examining the role of innate immunity in host-pathogen interactions. Pneumococcal disease remains a major cause of morbidity and mortality across the spectrum of age. Understanding the interaction between the immune system with the bacterium will allow us to appreciate how pneumococcus exists as a colonizer in the nasal mucosa but causes destructive invasive disease in the lungs. My work on the role of the host cytokine, macrophage migration inhibitory factor in both colonization and disease with the pathogen may lead to novel vaccination strategies, immune modulating therapies, or identification of patients at greatest risk for severe pneumococcal disease.